Engproc 67 00046
Engproc 67 00046
Engproc 67 00046
net/publication/384144688
CITATION READS
1 27
3 authors:
Tahmeena Khan
Integral University
116 PUBLICATIONS 784 CITATIONS
SEE PROFILE
All content following this page was uploaded by Tahmeena Khan on 19 September 2024.
Abstract: Thiosemicarbazone (TSC) derivatives and their complexes have emerged as versatile
medicinal agents. Now, the focus has shifted to targeted drug delivery and here, the application of
nanotechnology is being explored. Nanoparticles (NP) are being explored owing to their tremendous
medicinal applications. They are also known to overcome the water insolubility of medicinal agents
and have the ability to target specific targets. This article aims to explore the fabrication strategies
and applications of functionalized TSCs conjugated with NPs for improved therapeutic potential.
The studies were taken from the recent literature and indexed in leading databases. The literature
survey reveals the fabrication of TSCs with chitosan-coated superparamagnetic magnetite NPs,
which showed significant anti-proliferative activity against several cell lines. Similarly, cobalt oxide
nanoparticles conjugated with TSCs have been tested against the hepatic cancer cell line HepG2.
Other than anticancer activity, the functionalized nanoparticles have also been employed against drug-
resistant pathogens. To improve the oral bioavailability and pharmacological activity, nanoparticle-
based block polymers have been proposed to encapsulate the TSC moiety. The in vitro activity
of the fabricated NPs has been tested against Leishmania amazonensis. Against microphages, less
Citation: Veg, E.; Joshi, S.; Khan, T. cytotoxicity was observed. The article may shed light on the structure–bioactivity relationship of
Design and Fabrication of
novel nanocomposites derived from TSCs and NPs and their specific mechanisms of action.
Heterojunctions of
Thiosemicarbazones and Metal Oxide
Keywords: fabrication; thiosemicarbazone; nanocomposite; therapeutic agents
Nanoparticles in Search of Their
Medicinal Activity. Eng. Proc. 2024,
67, 46. https://doi.org/10.3390/
engproc2024067046
1. Introduction
Academic Editor: Juan Francisco
TSCs are Schiff bases that have been well-studied for antibacterial, antifungal, and
García Martín
anticancer properties [1]. TSCs (Figure 1) also act as chelating ligands and form a variety
Published: 19 September 2024 of complexes with metals, which increases their biological activities. TSCs are effective
chelating agents readily coordinating with metal ions to generate complexes that can alter
the biological activity of free ligands because of the electronic characteristics of the NNS
donor system and the diversity of chemical species that the system can produce [2]. TSCs
Copyright: © 2024 by the authors.
and other iron-chelating medications may have an impact on a number of proteins involved
Licensee MDPI, Basel, Switzerland.
in DNA replication and repair because they need iron as a cofactor. Through the alkylation
This article is an open access article
of the thiol on the top II-DNA complex, TSCs can stabilize the cleavable complex between
distributed under the terms and
topoisomerase II and DNA. Furthermore, TSCs can block the iron-containing enzyme
conditions of the Creative Commons
Attribution (CC BY) license (https://
ribonucleotide reductase via metal ion chelation, since iron has been demonstrated to be
creativecommons.org/licenses/by/
an important molecular target in cancer cell growth and the formation of reactive oxygen
4.0/).
species [3]. The antiviral efficacy of various TSCs appears to depend significantly on the
Eng. Proc. 2024, 67, 46 reactive oxygen species [3]. The antiviral efficacy of various TSCs appears to 2 ofdepend
8 s
nificantly on the inhibition of RNA polymerases, as shown by point mutations in the
zymes that result in drug-resistant virus types [4]. Major problems arise when using lar
inhibition of RNA polymerases, as shown by point mutations in the enzymes that result in
sized materials for the administration of drugs, like target-specific delivery, low bioav
drug-resistant virus types [4]. Major problems arise when using large-sized materials for
ability, inadequateofabsorption
the administration in the body, delivery,
drugs, like target-specific poor solubility, and potential
low bioavailability, negative effe
inadequate
ofabsorption
drugs [5].
in the body, poor solubility, and potential negative effects of drugs [5].
S
R1 R3
N
N N
H
R2 R4
Where R1,R2 = H/Alkyl/Aryl and
R3, R4= Alkyl/Aryl group
Figure
Figure 1. General
Generalstructure
structure of thiosemicarbazone.
of thiosemicarbazone.
A number of studies have reported the activity of TSCs against protozoa like Plas-
modium falciparum, Trichomonas vaginalis, etc. [12]. TSCs show inhibitory action cysteine
ptease and other enzymes expressed in all stages of T. cruzi, which are crucial for the
replication of intracellular parasites. Moreover, the anti-leishmania activity of TSCs has
also been reported. The activity of benzaldehyde TSC derivatives of limonene complexed
with copper has been tested against Leishmania amazonensis [13]. However, the hydrophobic
characteristic of benzaldehyde TSC affects its administration and bioavailability. Nanotech-
nology has been explored for the diagnosis and prevention of infectious diseases. The NPs
can overcome the problem of poor solubility in water and for being target-specific. The
NPs have been implemented for drug delivery systems to direct antileishmanial agents to
the cells of the reticuloendothelial system [14]. PLGA-PEG encapsulated miltefosine NPs
have been developed to target the macrophage of tissues infected with L. donovani [15].
NP-based block polymers to encapsulate the benzaldehyde TSC were synthesized and the
morphological parameters were studied by transmission and cryo-transmission electronic
microscopy. The entrapment encapsulation efficiency of the BZTS NPs was measured by
ultraviolet spectrophotometry. In vitro, activity of the NP suspensions against intracellular
amastigotes of Leishmania amazonensis and cytotoxic activity were also evaluated. Spherical
NPs were formed with varied sizes depending on the hydrophobic portion of the am-
phiphilic di-block copolymers [16]. Significant concentration-dependent inhibitory activity
against intracellular amastigotes was observed.
Therefore, nanomedicine is an emerging field describing the production and marketing
of nano-formulated drugs. Thus, using nanomaterials-based drug delivery systems for
targeting specific body sites would be able to solve these challenging issues [17,18]. By
producing particles at the nanoscale, the surface area is increased, and hence, the dissolution
rate of the drug increases, resulting in higher bioavailability. Recently, researchers have
developed different types of nanomaterial like nanocrystals for cancer treatment, metal
oxide NPs, iron oxide NPs (IONPs), and mesoporous silica NPs for drug and gene delivery
and target-specific delivery to develop improved, efficient, and biocompatible therapeutic
carriers [19]. Nanomedicine offers numerous appreciable applications as biochemical,
immunotherapeutic, chemotherapeutic agents, etc., and has been used for the treatment
of various diseases in recent times [20]. A wide range of sizes and shapes of metal-based
NPs have been studied concerning drug delivery and diagnosis. Some metal-based NPs
are Ni, Au, Ag, Fe2 O3 , CuO, ZnO, TiO2 , MgO, Al2 O3 NPs, etc. Metal-based NPs are
proven to provide a large surface area that allows the incorporation of large drug doses [21].
One major issue with the use of NPs is their strong affinity toward adhesion and aggregation.
To mitigate this tendency, surface modification of NPs using organic compounds has
been used to lower the surface energy of the particles and minimize their tendency to
agglomerate [22]. Therefore, to enhance the efficacy and biocompatibility of NPs, the
functionalization of these NPs with TSCs has been studied recently, which might be good
therapeutic agents for various diseases.
Chitosan (CS) and polyethylene glycol (PEG) polymers have been recently used in
the functionalization of metal oxide NPs, which play an important role in drug delivery
systems, bioimaging, etc. Chitosan is often used in combination with other polymers or
inorganic materials such as magnetic NPs [23].
The functionalization of the metal oxide NPs’ surface can be achieved either by ph-
ysisorption (non-covalent interaction) or by chemisorption (covalent bonding) with ligands.
Generally, ultrasonication methods have been used to functionalize nanoparticles [24].
Since different nanomaterials have distinct characteristics of chemical properties, different
functional groups can be bonded to their surfaces for the functionalization process. To
include an organic functional group (R-NH2 , R-COOH, etc.), homo- or hetero-bifunctional
cross-linkers are often required. For instance, amino silanes have been used as cross-linkers
to functionalize silica NPs. The amino group present on the surface of the NPs assisted
in their conjugation with the ligand. Similarly, noble metals, like Au, Pt, and metal oxide
NPs, can be functionalized by using crosslinkers with -SH, -NH2 , or -COOH groups that
Eng. Proc. 2024, 67, 46 4 of 8
facilitate covalent bonding with ligands [25]. The most commonly used cross-linkers are
amino acids like glutamic acid, aspartic acid, cysteine, lysine, etc. The carboxylic acid group
of these amino acids or amine and thiol functional groups in cysteine and lysine usually
bind to the surface of the NPs [26,27].
3. Design and Fabrication of the Heterojunction of TSCs with Metal Oxide NPs
The following methodology could be used to produce conjugated TSC with metal
oxide NPs:
1. In the first step, the TSC is synthesized via a condensation reaction with aromatic
aldehyde/ketone with thiosemicarbazide in the presence of an acidic medium using
an ethanol solvent system, and generally, the reaction takes place at 60 to 70 ◦ C for
3 to 4 h [28];
2. In the second step, metal oxide NPs are synthesized by using a bottom-up approach
like the sol-gel method, chemical precipitation method, or green synthesis [29];
3. In the third step, the synthesized NPs are functionalized by using suitable cross-
linkers like L-glutamic acid, L-aspartic acid, or 3-mercaptopropionic acid by using the
co-condensation method [30];
4. In the final step, the functionalized NPs can be conjugated with TSC by the ultrasonica-
tion method. Some studies, which have reported the methodology for the conjugation
of TSC with NPs, are as follows:
(a) To conjugate TSC to ZnO@Glu NPs, ZnO@Glu (500 mg) and TSC (200 mg)
were sonicated in 100 mL ethanol for 30 min and then stirred overnight at
40 ◦ C. The final product (ZnO@Glu–TSC) was separated by centrifugation,
washed with water and ethanol, and dried at 60 ◦ C for 6 h;
(b) Co3 O4 NPs were functionalized by glutamic acid (Glu) via a co-condensation
reaction to produce Co3 O4 @Glu. Finally, 500 mg of Co3 O4 @Glu-NP was mixed
with 200 mg of TSC in 150 mL of ethanol 96% and incubated in an ultrasonic
bath for 40 min at 45 ◦ C. The solution was placed on a heater at 40 ◦ C. After
24 h, the precipitate was separated by centrifugation and washed with ethanol
at 70 ◦ C to dry;
(c) For the synthesis of NiO@Glu-TSC, 300 mg of nickel chloride with 152 mg
of glutamic acid was dissolved in 150 mL of distilled water and incubated at
50 ◦ C, and then the NaOH (10%) solution was added to increase the pH to
about 11. The mixture was incubated at 80 ◦ C for 2 h. After that, the precipitate
was separated with a centrifuge and finally, the resulting precipitate was dried
at 70 ◦ C. In total, 500 mg of the previous sediment (NiO@Glu) with 200 mg
of thiosemicarbazide were dissolved in 150 mL of ethanol and placed in an
ultrasonic bath for 45 min. Then, the mixture was placed at 40 ◦ C for 24 h. The
precipitate was then separated by centrifugation and finally dried at 70 ◦ C.
The schematic representation is given in Figure 2 for the conjugation of TSCs with
metal oxide NPs.
Eng. Proc.
Eng. 2024,
Proc. 67,67,
2024, x FOR
46 PEER REVIEW 5 8of 8
5 of
O O
O OH
O O NH2
MONPs MONPs
+ HO OH O O
NH2
O OH
Metal oxide Nanoparticles L-Glutamic acid
(Glu) NH2
(MONPs)
MO@Glu NPs
O O O O
R1 R1
O OH H H
H2N N O NH N
N R2 N R2
NH2 NH2
+ S
MONPs S
O O MONPs O O
R1 R1
H H
O OH H2N N O NH N
N R2 N R2
NH2 NH2
S S
MO@Glu NPs THIOSEMICARBAZONEs MO@Glu-TSCs
(TSCs)
Figure
Figure2.2.Schematic
Schematic representation ofthe
representation of theconjugation
conjugationofofTSCs
TSCs with
with metal
metal oxide
oxide NPs.
NPs.
4.4.Some
SomeMedicinal
Medicinal Applications
Applications of
of TSCs
TSCsConjugated
Conjugatedwith
withFunctionalized
FunctionalizedMetal
Metal
Oxide NPs
Oxide NPs
A very recent study has reported the cytotoxic effect of CuO NPs conjugated with TSC
and A very recentwith
functionalized study has reported
glutamic the the
acid against cytotoxic effect
cancer cell lineofMCF-7
CuO and NPsnormal
conjugated with
cell lines
TSC and functionalized with glutamic acid against the cancer
HEK-293. The synthesis of CuO@glu/TSC was conducted by the co-precipitation method. cell line MCF-7 and normal
cell
Thelines HEK-293. The
dose-dependent synthesis of CuO@glu/TSC
antiproliferative activity showed was the ICconducted by the co-precipitation
50 value of 133.97 g/mL against
method.
the breast The dose-dependent
cancer cell line whereas antiproliferative
against the normal activity
cellshowed
line, the the
IC50ICwas50 value of 133.97
230.2 g/mL,
g/mL
which against
may be the breast cancer
attributed to thecell line whereas
nanoparticle against the
formulation [31].normal cell line,
In another theCo
study, IC350O4was
230.2 g/mL, which
NPs conjugated with may
TSCbe (Coattributed to the
3 O4 -TSC) were nanoparticle
tested against theformulation
HepG2 cell line. [31].By Inevalu-
another
ating the
study, Co3levels
O4 NPs of conjugated
the anti-apoptotic
with TSC Bcl2(Coand3O apoptotic
4-TSC) wereBax genes
testedusing
against certain primerscell
the HepG2
andBy
line. theevaluating
Real-Timethe PCR technique,
levels the effect of the
of the anti-apoptotic Bcl2conjugated
and apoptotic NPs Baxon apoptosis
genes using wascer-
evaluated. Compared to normal cells, cancer cells treated
tain primers and the Real-Time PCR technique, the effect of the conjugated NPs on apop-with NP had increased mean
expression
tosis of the Bax
was evaluated. gene. In cancer
Compared cells cells,
to normal treated with NP,
cancer cellsthe Bax/Bcl2
treated withexpression ratio
NP had increased
was greater than 1.0. Because of decreased expression of the anti-apoptotic
mean expression of the Bax gene. In cancer cells treated with NP, the Bax/Bcl2 expression Bcl2 gene and
increased expression of the apoptotic Bax gene, the heterojunction of Co3 O4 NPs with TSC
ratio was greater than 1.0. Because of decreased expression of the anti-apoptotic Bcl2 gene
exhibited more cytotoxic effects [32]. Nejabatdoust et al. synthesized ZnO NPs, which
and increased expression of the apoptotic Bax gene, the heterojunction of Co3O4 NPs with
were functionalized with glutamic acid and then conjugated to thiosemicarbazide (TSC)
TSC exhibited more cytotoxic effects [32]. Nejabatdoust et al. synthesized ZnO NPs, which
(ZnO@Glu–TSC) and after that, the conjugated NPs were evaluated against the Staphylo-
were
coccus functionalized with glutamic
aureus multidrug-resistant acid and
strain. The then conjugatedwas
ZnO@Glu–TSC to thiosemicarbazide
found to be 2–8 times (TSC)
(ZnO@Glu–TSC) and after that, the conjugated NPs were
more potent than the standard drug ciprofloxacin [33]. Hosseinkhah et al. synthesizedevaluated against the Staphylo-
coccus
NiO NPs aureus
andmultidrug-resistant
their functionalizationstrain. The ZnO@Glu–TSC
with thiosemicarbazide using was foundacid
glutamic to beas 2–8 times
a cross-
more
linker. potent than the standard
The characterization drug ciprofloxacin
of NiO@Glu-TSC [33]. Hosseinkhah
was performed using various et spectroscopic
al. synthesized
NiO NPs and
techniques liketheir functionalization
UV–Visible with thiosemicarbazide
Fourier Transform Infrared (FT–IR), X-ray usingdiffraction
glutamic (XRD),acid as a
cross-linker.
scanning electronThe characterization
microscopy (SEM), of and
NiO@Glu-TSC
energy dispersive was performed
X-ray analysis using various
(EDX). Using spectro-
the
MTT assay
scopic method,
techniques theUV–Visible
like cytotoxicityFourier
of the NiO@Glu-TSC
Transform Infrared NPs has(FT–IR),
been assessed
X-ray for AGS
diffraction
cells and
(XRD), normal electron
scanning fibroblastmicroscopy
cells. The IC(SEM),
50 values of 220
and and 390
energy respectively,
µg/mL, X-ray
dispersive analysisfor(EDX).
the
NiO@Glu-TSC NPs, indicated increased toxicity for AGS cells
Using the MTT assay method, the cytotoxicity of the NiO@Glu-TSC NPs has been assessed compared to normal fibrob-
lastAGS
for cellscells
[34]. and
In another
normalstudy, bifunctional
fibroblast cells. Thedextran-coated
IC50 valuesiron oxide
of 220 and NPs390 were produced
µg/mL, respec-
and preclinically assessed by Gholipour et al. for dual PET/MRI of biotin receptor-positive
tively, for the NiO@Glu-TSC NPs, indicated increased toxicity for AGS cells compared to
cancers. The functionalization of the NPs involved oxidizing the dextran coating layer to
normal fibroblast cells [34]. In another study, bifunctional dextran-coated iron oxide NPs
dialdehyde dextran. They were then coated with the cation chelator thiosemicarbazide and
were produced and preclinically assessed by Gholipour et al. for dual PET/MRI of biotin
the tumour-targeting compound biotin hydrazide [35]. Habibi et al. synthesized Fe3 O4 NPs
receptor-positive cancers. The functionalization of the NPs involved oxidizing the dextran
coating layer to dialdehyde dextran. They were then coated with the cation chelator thio-
semicarbazide and the tumour-targeting compound biotin hydrazide [35]. Habibi et al.
Eng. Proc. 2024, 67, 46 6 of 8
Table 1. Some FeO functionalized NPs used as a nanocarrier for drug delivery.
Habibi et al. studied the apoptotic action of magnetic Fe3 O4 NPs functionalized with
glutamic acid and 2-pyridinecarboxaldehyde thiosemicarbazone (PTSC) against the human
lung epithelial carcinoma A549 cell line and they found that Fe3 O4 @Glu/PTSC was shown
good anti-proliferative properties (IC50 = 135.6 µM/mL) while PTSC alone did not show
any activity [43]. Taati et al. studied that the Ag NPs functionalized by glutamine and
conjugated with thiosemicarbazide induce apoptosis in colon cancer cell lines. By using
an MTT assay, they found that Ag@Gln-TSC NPs were significantly more toxic for colon
cancer cells than normal fibroblast cells with IC50 of 88 and 186 µg/mL, respectively [44].
5. Conclusions
The nano-formulated TSCs have the potential to emerge as efficient, economical, safe,
and eco-friendly biologically active agents. This would lead to a novel and revolutionary
field of developing drugs with high bio-availability and efficient in vivo activity. The idea
of the development of nanomedicines is new and rapidly growing. Nanotechnology has
several advantages ranging from site-specificity to target-oriented drug delivery. Due
to enhanced modes of action, thiosemicarbazones are more effective against a variety of
diseases when nano-conjugated with metal oxide NPs.
Author Contributions: Investigation, formal analysis and writing—original draft, E.V.; writing—final
draft, S.J.; Conceptualization and Supervision, T.K. All authors have read and agreed to the published
version of the manuscript.
Funding: This research did not receive any external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data was created during the study.
Acknowledgments: The authors are thankful to the R&D cell of Integral University, Lucknow for
providing the Manuscript Communication Number (IU/R&D/2024-MCN0002830).
Conflicts of Interest: The authors declare no conflicts of interest.
Eng. Proc. 2024, 67, 46 7 of 8
References
1. Ibrahim, A.A.; Khathi, M.T.; Kareem, M.M. Spectroscopic Elucidation and Biological Assay of Hybrid Salicylaldehyde-
Thiosemicarbazone Nickel & Copper Complexes. J. Pharm. Negat. Results 2022, 13, 872–877.
2. Hashmi, K.; Gupta, S.; Siddique, A.; Khan, T.; Joshi, S. Medicinal applications of vanadium complexes with Schiff bases. J. Trace
Elem. Med. Biol. 2023, 79, 127245. [CrossRef] [PubMed]
3. Khan, T.; Raza, S.; Lawrence, A.J. Medicinal utility of thiosemicarbazones with special reference to mixed ligand and mixed metal
complexes: A Review. Russ. J. Coord. Chem. 2022, 48, 877–895. [CrossRef]
4. Khan, T.; Azad, I.; Ahmad, R.; Raza, S.; Dixit, S.; Joshi, S.; Khan, A.R. Synthesis, characterization, computational studies and
biological activity evaluation of Cu, Fe, Co and Zn complexes with 2-butanone thiosemicarbazone and 1, 10-phenanthroline
ligands as anticancer and antibacterial agents. Excli J. 2018, 17, 331. [PubMed]
5. Tandel, H.; Bhatt, P.; Jain, K.; Shahiwala, A.; Misra, A. In-vitro and in-vivo tools in emerging drug delivery scenario: Challenges
and updates. In In-Vitro and In-Vivo Tools in Drug Delivery Research for Optimum Clinical Outcomes; CRC Press: Boca Raton, FL,
USA, 2018; pp. 19–42.
6. Gupta, S.; Singh, N.; Khan, T.; Joshi, S. Thiosemicarbazone derivatives of transition metals as multi-target drugs: A review. Results
Chem. 2022, 4, 100459. [CrossRef]
7. Bhattarai, S.R.; Kc, R.B.; Kim, S.Y.; Sharma, M.; Khil, M.S.; Hwang, P.H.; Chung, G.H.; Kim, H.Y. N-hexanoyl chitosan stabilized
magnetic nanoparticles: Implication for cellular labeling and magnetic resonance imaging. J. Nanobiotechnol. 2008, 6, 1. [CrossRef]
8. Fischer, B.; Kryeziu, K.; Kallus, S.; Heffeter, P.; Berger, W.; Kowol, C.R.; Keppler, B.K. Nanoformulations of anticancer thiosemicar-
bazones to reduce methemoglobin formation and improve anticancer activity. RSC Adv. 2016, 6, 55848–55859. [CrossRef]
9. Barenholz, Y.C. Doxil® —The first FDA-approved nano-drug: Lessons learned. J. Control. Release 2012, 160, 117–134. [CrossRef]
10. Babak, M.V.; Ahn, D. Modulation of intracellular copper levels as the mechanism of action of anticancer copper complexes:
Clinical relevance. Biomedicines 2021, 9, 852. [CrossRef]
11. Gaur, K.; Vázquez-Salgado, A.M.; Duran-Camacho, G.; Dominguez-Martinez, I.; Benjamín-Rivera, J.A.; Fernández-Vega, L.;
Sarabia, L.C.; García, A.C.; Pérez-Deliz, F.; Román, J.A.M.; et al. Iron and copper intracellular chelation as an anticancer drug
strategy. Inorganics 2018, 6, 126. [CrossRef]
12. Walcourt, A.; Loyevsky, M.; Lovejoy, D.B.; Gordeuk, V.R.; Richardson, D.R. Novel aroylhydrazone and thiosemicarbazone iron
chelators with anti-malarial activity against chloroquine-resistant and-sensitive parasites. Int. J. Biochem. Cell Biol. 2004, 36,
401–407. [CrossRef] [PubMed]
13. Britta, E.A.; Barbosa Silva, A.P.; Ueda-Nakamura, T.; Dias-Filho, B.P.; Silva, C.C.; Sernaglia, R.L.; Nakamura, C.V. Benzalde-
hyde thiosemicarbazone derived from limonene complexed with copper induced mitochondrial dysfunction in Leishmania
amazonensis. PLoS ONE 2012, 7, e41440. [CrossRef] [PubMed]
14. Want, M.Y.; Islamuddin, M.; Chouhan, G.; Dasgupta, A.K.; Chattopadhyay, A.P.; Afrin, F. A new approach for the delivery
of artemisinin: Formulation, characterization, and ex-vivo antileishmanial studies. J. Colloid Interface Sci. 2014, 432, 258–269.
[CrossRef] [PubMed]
15. Kumar, R.; Sahoo, G.C.; Pandey, K.; Das, V.N.R.; Topno, R.K.; Ansari, M.Y.; Das, P. Development of PLGA–PEG encapsulated
miltefosine based drug delivery system against visceral leishmaniasis. Mater. Sci. Eng. C 2016, 59, 748–753. [CrossRef]
16. Britta, E.A.; da Silva, C.C.; Rubira, A.F.; Nakamura, C.V.; Borsali, R. Generating nanoparticles containing a new 4-
nitrobenzaldehyde thiosemicarbazone compound with antileishmanial activity. Mater. Sci. Eng. C 2016, 69, 1159–1166.
[CrossRef]
17. Patra, J.K.; Das, G.; Fraceto, L.F.; Campos, E.V.R.; Rodriguez-Torres, M.D.P.; Acosta-Torres, L.S.; Shin, H.S. Nano based drug
delivery systems: Recent developments and future prospects. J. Nanobiotechnol. 2018, 16, 71. [CrossRef]
18. Bhalani, D.V.; Nutan, B.; Kumar, A.; Singh Chandel, A.K. Bioavailability enhancement techniques for poorly aqueous soluble
drugs and therapeutics. Biomedicines 2022, 10, 2055. [CrossRef]
19. Elahi, N.; Rizwan, M. Progress and prospects of magnetic iron oxide nanoparticles in biomedical applications: A review. Artif.
Organs 2021, 45, 1272–1299. [CrossRef]
20. Rahman, M.A.; Saikat, A.S.M.; Rahman, M.S.; Islam, M.; Parvez, M.A.K.; Kim, B. Recent update and drug target in molecular and
pharmacological insights into autophagy modulation in cancer treatment and future progress. Cells 2023, 12, 458. [CrossRef]
21. Sodhi, R.K.; Paul, S. Metal complexes in medicine an overview and update from drug design perspective. Cancer Ther. Oncol. Int.
J. 2019, 14, 25–32. [CrossRef]
22. Mallakpour, S.; Madani, M. A review of current coupling agents for modification of metal oxide nanoparticles. Prog. Org. Coat.
2015, 86, 194–207. [CrossRef]
23. Agnihotri, S.A.; Mallikarjuna, N.N.; Aminabhavi, T.M. Recent advances on chitosan-based micro-and nanoparticles in drug
delivery. J. Control. Release 2004, 100, 5–28. [CrossRef]
24. Afzal, A.; Nawfal, I.; Mahbubul, I.M.; Kumbar, S.S. An overview on the effect of ultrasonication duration on different properties
of nanofluids. J. Therm. Anal. Calorim. 2019, 135, 393–418. [CrossRef]
25. Azadmanjiri, J.; Kumar, P.; Srivastava, V.K.; Sofer, Z. Surface functionalization of 2D transition metal oxides and dichalcogenides
via covalent and non-covalent bonding for sustainable energy and biomedical applications. ACS Appl. Nano Mater. 2020, 3,
3116–3143. [CrossRef]
Eng. Proc. 2024, 67, 46 8 of 8
26. Daima, H.K.; Navya, P.N.; Lichtfouse, E. (Eds.) Nanozymes for Environmental Engineering; Springer: Berlin/Heidelberg, Germany,
2021.
27. Casettari, L.; Vllasaliu, D.; Lam, J.K.; Soliman, M.; Illum, L. Biomedical applications of amino acid-modified chitosans: A review.
Biomaterials 2012, 33, 7565–7583. [CrossRef] [PubMed]
28. Ebrahimi, H.P.; Hadi, J.S.; Alsalim, T.A.; Ghali, T.S.; Bolandnazar, Z. A novel series of thiosemicarbazone drugs: From synthesis to
structure. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2015, 137, 1067–1077. [CrossRef] [PubMed]
29. Soltys, L.; Olkhovyy, O.; Tatarchuk, T.; Naushad, M. Green synthesis of metal and metal oxide nanoparticles: Principles of green
chemistry and raw materials. Magnetochemistry 2021, 7, 145. [CrossRef]
30. Wang, Z.; Yao, B.; Xiao, Y.; Tian, X.; Wang, Y. Fluorescent quantum dots and its composites for highly sensitive detection of heavy
metal ions and pesticide residues: A review. Chemosensors 2023, 11, 405. [CrossRef]
31. Shafiei, I.; Tavassoli, S.P.; Rahmatollahi, H.R.; Ghasemian, R.; Salehzadeh, A. A novel copper oxide nanoparticle conjugated by
thiosemicarbazone promote apoptosis in human breast cancer Cell line. J. Clust. Sci. 2022, 33, 2697–2706. [CrossRef]
32. Jarestan, M.; Khalatbari, K.; Pouraei, A.; Sadat Shandiz, S.A.; Beigi, S.; Hedayati, M.; Majlesi, A.; Akbari, F.; Salehzadeh, A.
Preparation, characterization, and anticancer efficacy of novel cobalt oxide nanoparticles conjugated with thiosemicarbazide.
3 Biotech 2020, 10, 230. [CrossRef]
33. Nejabatdoust, A.; Zamani, H.; Salehzadeh, A. Functionalization of ZnO nanoparticles by glutamic acid and conjugation with
thiosemicarbazide alters expression of efflux pump genes in multiple drug-resistant Staphylococcus aureus strains. Microb. Drug
Resist. 2019, 25, 966–974. [CrossRef]
34. Hosseinkhah, M.; Ghasemian, R.; Shokrollahi, F.; Mojdehi, S.R.; Noveiri, M.J.S.; Hedayati, M.; Rezaei, M.; Salehzadeh, A. Cytotoxic
potential of nickel oxide nanoparticles functionalized with glutamic acid and conjugated with thiosemicarbazide (NiO@ Glu/TSC)
against human gastric cancer cells. J. Clust. Sci. 2022, 33, 2045–2053. [CrossRef]
35. Gholipour, N.; Akhlaghi, M.; Kheirabadi, A.M.; Geramifar, P.; Beiki, D. Development of Ga-68 labeled, biotinylated thiosemi-
carbazone dextran-coated iron oxide nanoparticles as multimodal PET/MRI probe. Int. J. Biol. Macromol. 2020, 148, 932–941.
[CrossRef] [PubMed]
36. Habibi, A.; Bakhshi, N.; Amirmozafari, N. Iron oxide nanoparticles conjugated to thiosemicarbazone reduce the survival of cancer
cells by increasing the gene expression of microRNA let-7c in lung cancer A549 cells. Arch. Iran. Med. 2022, 25, 807. [CrossRef]
37. Soares, P.I.; Sousa, A.I.; Silva, J.C.; Ferreira, I.M.; Novo, C.M.; Borges, J.P. Chitosan-based nanoparticles as drug delivery systems
for doxorubicin: Optimization and modelling. Carbohydr. Polym. 2016, 147, 304–312. [CrossRef]
38. Bajpai, A.K.; Gupta, R. Magnetically mediated release of ciprofloxacin from polyvinyl alcohol based superparamagnetic nanocom-
posites. J. Mater. Sci. Mater. Med. 2011, 22, 357–369. [CrossRef]
39. Gaihre, B.; Khil, M.S.; Lee, D.R.; Kim, H.Y. Gelatin-coated magnetic iron oxide nanoparticles as carrier system: Drug loading and
in vitro drug release study. Int. J. Pharm. 2009, 365, 180–189. [CrossRef] [PubMed]
40. Arias, J.L.; López-Viota, M.; Delgado, Á.V.; Ruiz, M.A. Iron/ethylcellulose (core/shell) nanoplatform loaded with 5-fluorouracil
for cancer targeting. Colloids Surf. B Biointerfaces 2010, 77, 111–116. [CrossRef] [PubMed]
41. Tong, Q.; Li, H.; Li, W.; Chen, H.; Shu, X.; Lu, X.; Wang, G. In vitro and in vivo anti-tumor effects of gemcitabine loaded with a
new drug delivery system. J. Nanosci. Nanotechnol. 2011, 11, 3651–3658. [CrossRef]
42. Losic, D.; Yu, Y.; Aw, M.S.; Simovic, S.; Thierry, B.; Addai-Mensah, J. Surface functionalisation of diatoms with dopamine
modified iron-oxide nanoparticles: Toward magnetically guided drug microcarriers with biologically derived morphologies.
Chem. Commun. 2010, 46, 6323–6325. [CrossRef]
43. Habibi, A.; Sadat Shandiz, S.A.; Salehzadeh, A.; Moradi-Shoeili, Z. Novel pyridinecarboxaldehyde thiosemicarbazone conjugated
magnetite nanoparticulates (MNPs) promote apoptosis in human lung cancer A549 cells. JBIC J. Biol. Inorg. Chem. 2020, 25, 13–22.
[CrossRef] [PubMed]
44. Taati, H.; Sangani, H.; Davoudi, A.; Safabakhsh Kouchesfahani, S.; Hedayati, M.; Tarashandeh Hemmati, S.; Salehzadeh, A. Silver
nanoparticle functionalized by glutamine and conjugated with thiosemicarbazide induces apoptosis in colon cancer cell line.
Sci. Rep. 2024, 14, 3809. [CrossRef] [PubMed]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.
Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.
Alternative Proxies: